Method for continuously acylating chromanol ester derivatives

ABSTRACT

A process is described for continuously preparing chromanol ester derivatives, in particular for continuously preparing carboxylic esters of tocopherols and tocotrienols by continuous acylation with carboxylic acids or carboxylic anhydrides.

The present invention relates to a process for continuously preparingchromanol ester derivatives, in particular for continuously preparingcarboxylic esters of tocopherols and tocotrienols by continuousacylation with carboxylic acids or carboxylic anhydrides.

Compounds having vitamin E activity, such as the naturally occurringchromanol derivatives of the tocopherol and tocotrienol group, areimportant fat-soluble antioxidants. A vitamin E deficiency in humans andanimals leads to pathophysiological conditions. Vitamin E compoundstherefore have a high economic value as additives in the food and feedsectors, in pharmaceutical formulations and in cosmetics applications.The compounds having vitamin E activity, in particular α-tocopherol, areused for this principally in the form of their acetate esters. Aneconomic process for preparing chromanol ester derivatives is thereforeof high importance.

It is known to react tocopherol derivatives batchwise with aceticanhydride to give the corresponding acetate esters.

EP 850 937 describes in the examples a batchwise process for preparingα-tocopherol acetate by heating under reflux α-tocopherol with aceticanhydride in a stirred flask having an attached reflux condenser. Thereaction discharge is then worked up by distillation.

DE 19 603 142 describes a process for preparing d1-α-tocopherol acetateby acid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) withphytol or isophytol (IP) in a solvent at elevated temperature andsubsequent acetylation of the resultant tocopherol. The tocopherol isacetylated by acid-catalyzed reaction with excess acetic anhydride. Thereaction discharge is worked up by fractional distillation under reducedpressure. For the continuous reaction of 2,3,5-trimethylhydroquinonewith phytol, a reaction column is proposed into which a mixture ofcyclic carbonate, the catalyst, TMH and IP are fed in laterally. Thehydrocarbon and the water formed are removed at the top of the columnand hot cyclic carbonate and vitamin E are taken off from the bottom. Nodescription is given of the process design of the subsequent acylation.An example mentions that the tocopherol isolated after phase separationwas esterified with acetic anhydride.

A process for preparing d1-α-tocopherol or d1-α-tocopherol acetate byacid-catalyzed reaction of 2,3,5-trimethylhydroquinone (TMH) with phytolor isophytol (IP) in the presence of a mixture of orthoboric acid andcertain aliphatic di- or tricarboxylic acids with or without subsequentesterification with acetic anhydride is described in DE 42 08 477.According to DE 42 08 477, the tocopherol prepared is converted in asimilar manner to DE 19 603 142 into tocopherol acetate batchwise withexcess acetic anhydride under acid catalysis and purified by fractionaldistillation under a greatly reduced pressure. The initial molar ratioof acetic anhydride/tocopherol was greater than 1.3 mol/mol and the acidconcentration was approximately 0.055 mol % based on tocopherol.

EP 0 784 042 claimed hydrogen bis(oxalato)borate as protic acid catalystfor the Friedel-Crafts condensation of trimethylhydroquinone withisophytol and the acylation of phenols, for example tocopherol. In anexample the acylation of tocopherol is described. For this, tocopherolwas charged into a flask together with acetic anhydride and hydrogenbis(oxalato)borate and the reaction mixture was heated to reflux for onehour under an argon atmosphere. The initial molar ratio of aceticanhydride/tocopherol was greater than 1.1 mol/mol and the borateconcentration was approximately 0.5 mol %, based on tocopherol. Afterconcentration on a rotary evaporator, tocopherol acetate was obtained ina purity of 87% at a yield of 92%. This batch process has thedisadvantage that both yield and purity are still not satisfactorilyhigh. In addition, carrying out the reaction in an argon atmosphere isassociated with high costs for industrial production.

JP 49 055 633 describes the batchwise preparation of tocopherol acetateby acylation of tocopherol with acetic anhydride in the presence ofinorganic solid acids which are insoluble in the reaction mixture. Inthe process, tocopherol and acetic anhydride in the solvent toluene areheated in the presence of the catalyst for about 4 hours under reflux, aproduct purity of about 91% being achieved. As an example of thecatalyst, SiO₂/Al₂O₃ is mentioned. Disadvantages of the process are thelow space-time yields and the low product purities.

The acylation of tocopherol with acetic anhydride in the presence of amixture of hydrochloric acid and zinc or zinc chloride is described inJP 56 073 081. According to this process, tocopherol is heated withacetic anhydride and the catalyst mixture at from 10 to 30° C. for from0.5 to 2 hours. The catalyst is then removed and the reaction mixture iswashed with water. Hydrochloric acid is used at a concentration of from0.02 to 0.06 mol % based on tocopherol, the zinc is used at aconcentration of from 0.01 to 0.2 mol % based on tocopherol and the zincchloride is used at a concentration of from 0.001 to 0.1 mol % based ontocopherol. Acetic anhydride is used at a from 1.2 to 1.5 times molarexcess. The process gives tocopherol acetate at a yield of 92.5% basedon tocopherol. The complex workup, the batchwise reaction procedure andthe solids handling cause a low space-time yield in this process,despite the short reaction time.

DE 2 208 795 describes the reaction of trimethylhydroquinone withisophytol in the presence of a mixture of a Lewis acid and a protic acidin an inert solvent. The catalyst system which can be used is, forexample, a mixture of zinc chloride with NaHSO₄, H₂SO₄ orp-toluenesulfonic acid. Optionally, the reaction discharge can bereacted with acetic anhydride without further workup. For this aceticanhydride is added to the reaction mixture and heated under reflux forabout 6 hours. A disadvantage of this process is the low space-timeyield for the acylation.

A continuous process for reacting trimethylhydroquinone with isophytol,phytol or phytadienes in the presence of acid condensation catalysts ina packed column is described in U.S. Pat. No. 3,444,213. In this processthe reactants, optionally premixed or dissolved in an inert solvent, areapplied to the top of a heated column and the resultant reaction wateris evaporated via the top of the column. The column, however, is only aheated tubular reactor without evaporator, and not a reactivedistillation column. The product arising at the bottom of the column isreacted in the course of one hour batchwise with acetic anhydride in thesolvent pyridine. A disadvantage of this process is the low space-timeyield of the acylation and the use of a solvent.

A further continuous process for reacting trimethylhydroquinone withisophytol is described in CS 205 951. In this patent also, the acylationis performed batchwise using acetic anhydride.

All known processes of the prior art for acetylating tocopherolderivatives have the disadvantage of high residence times and thus lowspace-time yields and high capital costs. In all cases the tocopherolderivative, in the absence or presence of a catalyst, is reactedbatchwise with acetic anhydride and the reaction mixture is worked up bydistillation. In this case, firstly the acetic acid and the aceticanhydride are removed at low vacuum and the acetate of the tocopherolderivative is then purified by distillation under a high vacuum.

Furthermore, the yields of these processes, at about from 92 to 95%, areinsufficiently satisfactory. The acetic anhydride is always used in arelatively high excess of at least 1.2 mol per mole of tocopherolderivative, in order to achieve a sufficient conversion rate at anacceptable reaction time. As implied by EP 0 784 042, reduction in theexcess of acetic anhydride is only possible if the acid concentration isconsiderably increased. However, this leads to an increased formation ofbyproducts and thus to decreased yields and product purity.

It is an object of the present invention, therefore, to provide afurther process for preparing chromanol ester derivatives havingadvantageous properties, which process no longer exhibits thedisadvantages of the prior art and which gives chromanol esterderivatives in high yields and high space-time yields.

We have found that this object is achieved by a process for continuouslypreparing chromanol ester derivatives of the formula I,

where

R1, R2, R3, R4, R5, R6, R7 and R8 independently of one another arehydrogen or an unsubstituted or substituted, branched or unbranchedC₁-C₁₀-alkyl radical and

the dashed bonds are a possible additional C—C bond,

by reacting continuously fed chromanol derivatives of the formula II

with continuously fed acylating agent selected from the group consistingof carboxylic acids of the formula IIIa

R8-COOH  IIIa

and carboxylic anhydrides of the formula IIIb,

where

R9 is hydrogen or an unsubstituted or substituted, branched orunbranched C₁-C₁₀-alkyl radical,

in a reactor

and continuously removing the reaction products from the reactor.

An unsubstituted or substituted, branched or unbranched C₁-C₁₀-alkylradical is, for the radicals R1, R2, R3, R4, R5, R6, R7, R8 and R9independently of one another, for example, unsubstituted or substitutedmethyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, heptyl, octyl, nonylor decyl, preferably unsubstituted or substituted C₁-C₄-alkyl, forexample methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl ortert-butyl.

The type of substituents is not critical. The C₁-C₁₀-alkyl radicals,depending on free bonds available, can contain up to 6 substituents,preferably selected from the group consisting of —NO₂, —NH₂, —OH, —CN,—COOH, or halogen, in particular F or Cl.

In a preferred embodiment the branched or unbranched C1-C10-alkylradicals of the radicals R1, R2, R3, R4, R5, R6, R7, R8 and R9 are notsubstituted.

Particularly preferred radicals for R4, R5, R6 and R7 are independentlyof one another hydrogen or methyl, in particular methyl.

Particularly preferred radicals for R1, R2 and R3 are independently ofone another hydrogen or methyl.

Particularly preferred radicals for R8 are methyl or ethyl, inparticular methyl.

Particularly preferred radicals for R9 are ethyl or methyl.

In a preferred embodiment of the inventive process, the chromanolderivatives of the formula II are tocopherol derivatives and tocotrienolderivatives having vitamin E activity, in particular the naturallyoccurring tocopherols and tocotrienols.

For the preferred naturally occurring tocopherols and tocotrienols, informula II the radicals R4 to R7 are methyl. The group of tocopherols(IIa-d) has a saturated side chain, and the group of the tocotrienols(IIe-h) have an unsaturated side chain:

Particularly preferably, in the inventive process α-tocopherol of theformula IIa is used as chromanol derivative of the formula II.

The chromanol derivatives of the formula II used in the inventiveprocess, in particular the preferred tocopherols and tocotrienols of theformulae IIa to IIh can be used as individual compounds which can bepresent in any desired purity. Generally, the purity of individualtocopherols and tocotrienols is from 90% to 97%, but purer compounds andless pure crude products can also be used. The compounds can also beused as a mixture of different chromanol derivatives of the formula IIand the inventive process correspondingly leads to a mixture ofchromanol ester derivatives of the formula I. This can be the case, forexample, when tocopherols or tocotrienols are used from natural sourceswithout further separation of the individual tocopherols andtocotrienols. The chromanol derivatives of the formula II can beenantiomerically pure, a racemic mixture, or a diastereomer mixture.

The chromanol derivatives of the formula II can be chemically preparedor isolated from natural sources, for example the evaporator condensatesproduced in vegetable oil deodorization and purified, as described inUllmann's Encyclopedia of Industrial Chemistry, Vol. A 27 (1996), VCHVerlagsgesellschaft, Chapter 4., 478-488, Vitamin E.

The carboxylic acids of the formula IIIa or carboxylic anhydrides of theformula IIIb used as acylating agents in the inventive process can beused as individual substances or as mixtures.

In a preferred embodiment, the acylating agents used are the carboxylicanhydrides of the formula IIIb.

The carboxylic anhydrides of the formula IIlb can be used as purecarboxylic anhydrides or as mixed carboxylic anhydrides. In a preferredembodiment, pure carboxylic anhydrides are used, so that R8=R9.Particular preference is given to the acetylation using acetic anhydrideas carboxylic anhydride of the formula IIIb where R8=R9=methyl.

In the inventive process the reactants, the chromanol derivatives of theformula II and the acylating agents, selected from the group consistingof carboxylic acids of the formula IIIa and carboxylic anhydrides of theformula IIIb, are fed continuously to a reactor, reacted in the reactorand then the reaction products are continuously removed from thereactor.

In the case of reactions having a high initial rate, it can beadvantageous to connect upstream of the reactor a further preliminaryreactor in which a partial conversion already takes place. It can alsobe advantageous to mix the reactants before feeding into the reactor, sothat here also a partial conversion takes place.

The term “reacted in a reactor” therefore means that in this reactorconversion of the reactants still takes place. This conversion in thereactor can, for example when a preliminary reactor is connectedupstream, be at least 1%, preferably at least 20%, particularlypreferably at least 50%, very particularly preferably at least 80%, ofthe conversion rate which is achievable overall. In a preferredembodiment, the total achievable conversion occurs in the reactor.

When the reactants are fed and reacted, in addition solvents can beused. Particularly advantageously, however, the process may be carriedout without addition of solvents.

The inventive process may be particularly advantageously carried out bycontinuously removing at least one reaction product from the reactionmixture during the reaction in the reactor, that is to saysimultaneously with the reaction. Accordingly, the water formed from theacylating agent (when carboxylic acids of the formula IIIa are used asacylating agent) or the resultant carboxylic aci R9-COOH (whencarboxylic anhydrides of the formula IIIb are used as acylating agent)or the resultant chromanol ester derivatives of the formula I or bothare removed from the reaction mixture during the reaction.

In a preferred embodiment, only water or the carboxylic acid R9-COOH isremoved from the reaction mixture. This removal is also preferablyperformed continuously.

There are many reactor designs which come into consideration for thepreferred inventive process. Preferred reactors should have the propertyof enabling continuous reaction with simultaneous removal of at leastone reaction product. For example, reactors which can be used are stillshaving an attached column, divided wall columns, extraction columns,membrane reactors or reaction columns.

In a particularly preferred embodiment of the inventive process, thereaction is performed in a reaction column as reactor.

As described above, it can be advantageous to connect upstream of thisreaction column a reactor (preliminary reactor) in which a portion ofthe conversion already takes place. In a particularly preferredembodiment, the reaction is performed in a reactor, in particular in areaction column.

A reaction column, which can be designed in very different ways, has theproperty as a reactor of enabling simultaneously a reaction of reactantsand the thermal removal of at least one reaction product.

Preferably the reaction column consists of a bottom and a superstructurewhich enables rectification, for example a fractionation column.

In this preferred embodiment, using a reaction column it is furtheradvantageous to set the reaction parameters in such a manner that

A the chromanol derivatives of the formula II react with the acylatingagent on the internals and possibly in the bottom phase of the reactioncolumn,

B the H₂O formed in the reaction with the acylating agent (use ofcarboxylic acids of the formula IIIa as acylating agent) or thecarboxylic acid R9-COOH formed (use of carboxylic anhydrides of theformula IIIb as acylating agent) is continuously removed with theoverhead stream of the reaction column and

C the chromanol ester derivatives of the formula I formed in thereaction are continuously removed with the bottom stream of the reactioncolumn.

Depending on the type of design of the reaction column and the reactantsused, this is achieved by varying reaction parameter settings. Suitablereaction parameters are, for example, temperature, pressure, refluxratio in the column, design of the column, heat transfer and residencetime, in particular in the bottom phase, energy input or the molar ratioof the reactants, which can be optimized by those skilled in the art byroutine experiments so that the features A, B and C are achieved.

Typically, in the inventive process, the pressure at the column top isset so that the temperature in the bottom is from 100 to 300° C.preferably from 130 to 180° C.

The residence time in the reaction column is typically from 15 minutesto 6 hours, preferably from 30 minutes to 3 hours.

The initial ratio of the reactants is not critical, the molar ratio ofacylating agent, that is to say the carboxylic acids of the formula IIIaor the carboxylic anhydrides of the formula IIIb to the chromanolderivative of the formula II is usually from 1.0 to 5.0, preferably from1.0 to 1.3.

The inventive process may be carried out particularly advantageously ifthe reaction is carried out in the presence of a catalyst.

A catalyst is a substance which is able to accelerate the acylation ofchromanol derivatives of the formula II.

Preferred catalysts are acid or basic acylation catalysts, for example,sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid,acetates, zinc chloride, triethylamine, pyridine, tertiary bases,hydrogen bis(oxalato)borate, acid or basic ion exchangers, zeolites,SiO₂/Al₂O₃ or inorganic solid acids.

Particularly preferred catalysts are homogeneous basic or acidcatalysts, in particular sulfuric acid or phosphoric acid, andheterogeneous catalysts, in particular acid ion exchangers or acidzeolites, which are introduced in a targeted manner into the reactionzone.

The homogeneous catalysts have the advantage that they can be pumped inthe liquid state into the fractionation column. The heterogeneouscatalysts have the advantage that they do not lead to contamination ofthe product or to impairment of the color index of the product duringworkup.

The homogeneous catalysts are preferably used in dilute form. Thus, forexample, sulfuric acid and phosphoric acid are typically used at aconcentration from 0.01 to 50%, preferably at a concentration from 0.1to 1.0%. The amount of the homogeneous catalysts is preferablydimensioned such that their concentration is from 0.001 to 1.0 mol %,based on the chromanol derivative of the formula II, preferably from0.01 to 0.1 mol %, based on the chromanol derivative of the formula II.

The heterogenous catalysts are preferably integrated into thefractionation column internals.

In a particularly preferred embodiment of the inventive process, thereaction column internals used are column trays below the highest feedpoint for the reactants, and are structured packings above the highestfeed point for the reactants. Particularly advantageous column traysmake high residence time of the liquid possible, with the residence timeon the reaction column internals preferably being at least 30 min.

Preferred column trays are, for example, valve trays, preferablybubble-cap trays, or related types, for example tunnel trays or Thormanntrays.

Preferred structured packings are, for example, structured packings ofthe following types: Melapack^((R)) (Sulzer), BX^((R)) (Sulzer),B1^((R)) (Montz) or A3^((R)) (Montz) or packings of comparable designs.

In a further particularly preferred embodiment of the inventive process,the higher-boiling reactant, if appropriate together with thehomogeneous catalyst, is fed into the reaction column above thelower-boiling reactant.

Particularly advantageously, the process may be carried out by the heatbeing fed into the reaction column, in addition to an evaporator, viaheat exchangers mounted externally to the reaction column, or via heatexchangers situated directly on the column trays.

In addition, the introduction of a stripping gas, preferably nitrogen orcarbon dioxide, into the reaction column is advantageous.

This facilitates the removal of water or the resultant carboxylic acidR9-COOH.

In addition, the inventive process may be carried out advantageously byremoving excess acylating agent, that is to say the carboxylic acid ofthe formula IIIa or the carboxylic anhydride of the formula IIIb, fromthe effluent bottom stream in a downstream evaporator, and recirculatingit to the column with or without ejection of a substream. As a result,high yields are achieved based on the acylating agent (carboxylic acidof the formula IIIa or carboxylic anhydride of the formula IIIb).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 illustrate two particularly advantageous embodiments ofthe process.

DETAILED DESCRIPTION OF THE DRAWINGS

A particularly advantageous embodiment of the inventive process will bedescribed below by way of example with reference to FIG. 1:

The inventive process is preferably carried out in such a manner thatthe chromanol derivative of the formula II, the acylating agent(carboxylic acids of the formula IIIa or carboxylic anhydrides of theformula IIIb) with or without the catalyst is applied via the feeds (3),(1) and (2) to the internals of a fractionating column (4) functioningas a reaction column. It is advantageous here, but not obligatory, ifthe higher-boiling reactant is fed continuously into the fractionatingcolumn (4) separately or together with the catalyst above thelower-boiling reactant. On the fractionating column internals, thechromanol derivative of the formula II then reacts with the acylatingagent, with a superimposed distillation. As a result the water formingfrom the carboxylic acid of the formula IIIa or the carboxylic acidR9-COOH forming from the carboxylic anhydride of the formula IIIb isconstantly removed from the reaction equilibrium.

The chromanol ester derivatives of the formula I pass through thesuperimposed distillation into the bottom (36) of the fractionatingcolumn and are taken off via the stream (14).

When acetic anhydride or priopionic anhydride is used as carboxylicanhydride of the formula IIIb, it is very advantageous if thiscarboxylic anhydride is introduced into the column (4) in vaporous form,since cleavage in the bottom (36) of the column at high temperatures andformation of byproducts is further reduced to avoided.

In addition it has proved to be highly advantageous if the heat is fedinto the reaction system consisting of the column bottom (36) andfractionating column (4) and possibly also vessel (30) not just via theevaporator (13) but additionally via external heat exchangers (37) orvia heat exchangers situated directly on the column internals (16).

The reaction column (4) consists of two segments. The upper segment (17)is preferably packed with structured packings, and the lower segment(16) is preferably packed with column trays. It is advantageous todimension the upper segment (17), depending on the separation effort, insuch a manner that the acylating agent is completely retained and isrecirculated to the lower segment (16) for reaction.

The water or the carboxylic acid R9-COOH formed leaves the columntogether with any low-boilers present in the reactants as contaminant orformed during the reaction as byproduct via the overhead stream (6) andpasses into the condenser (7) where the condensable constituents of thisvapor stream are condensed out. A part of the condensate is reapplied tothe column as reflux (10) and the other part (11) is taken off.

The reflux ratio is not critical. Preferably, a reflux ratio from 1 to20, particularly preferably from 2 to 4, should be set. However, it isalso possible to take off the condensate completely (reflux ratio=0) ifthe higher-boiling reactant is applied at the upper end of the column.

The distillate (11) generally consists of water or the carboxylic acidR9-COOH in a purity greater than 99%. In the presence of low-boilingcontaminants, it can be advantageous to take off the carboxylic acidR9-COOH at high purity via an additional side stream takeoff (38). Forthis, the upper column segment (17) must be dimensioned appropriately.

The pressure at the column top (6) is preferably set in such a mannerthat the temperature in the bottom (36) is from 100 to 300° C. inparticular from 130 to 180° C. Depending on the system of substances,this can be achieved using a vacuum pump (9) and/or a pressureregulating device (39).

The reaction product collects in the bottom (36) of the column (4) andis taken off by means of a pump (12) via the bottom stream (14) togetherwith the unreacted reactants, essentially together with excesscarboxylic acid of the formula IIIa or excess carboxylic anhydride ofthe formula IIIb. A part of the bottom stream (14) is evaporated by anevaporator (13) and fed into the column via the vapor line (15). By thismeans the vapors required for the distillation are produced. The crudeproduct is fed via the product line (35) to a downstream evaporator(19), which frees the crude product from low-boilers, in particular fromunreacted carboxylic acid of the formula IIIa, or unreacted carboxylicanhydride of the formula IIIb.

It is possible, for removal of the resultant water or the carboxylicacid R9-COOH formed, to feed additionally an inert gas (41) into thebottom of the column.

The evaporator (19) is generally operated, using a vacuum unit (22) at alower pressure than the column (4), the pressure being set in such amanner that the vapor stream (40) comprises only small amounts ofproduct of value, and the product stream (34) comprises only smallamounts of low-boilers. The vapor stream (40) of the evaporator (19) iscondensed out in a condenser (21) and fed via the line (25) of thevessel (23).

In the case of mixtures of substances in which the carboxylic acid ofthe formula IIIa or water or the carboxylic anhydride of the formulaIIIb or the carboxylic acid R9-COOH forms a miscibility gap with theminor components, the vessel (23) is designed as a phase-separationvessel.

In this case it is advantageous to eject the minor components using thepump (27) via the byproduct line (26) and in this manner to increase theselectivity and to prevent the accumulation of byproducts. The phasecomprising unreacted reactants is recirculated to the column using apump (24) via the line (28). If the condensed vapors (25) form a singlephase, it can be advantageous to prevent an accumulation of byproductsby ejecting a part stream via the line (26).

Via the bottom stream (34) of the evaporator (19), the product of valuefreed from low-boilers is withdrawn and, if appropriate, fed to furtherpurification stages such as short-path evaporators and/or moleculardistillation.

The amounts added are preferably selected in such a manner that thestoichiometric ratio of acylating agent to the chromanol derivative ofthe formula II is from 1.0 to 5.0, preferably from 1.0 to 1.3, and acatalyst content is set from 0.001 to 1.0 mol %, preferably from 0.01 to0.1 mol %, based on the chromanol derivative to be reacted.

The residence time of the reaction mixture in the reactor systemconsisting of bottom phase (36) and fractionating column (4) with orwithout vessel (30) is typically from 15 minutes to 6 hours, preferablyfrom 20 minutes to 2 hours. This residence time may advantageously beachieved by trays (16, 17) having a high liquid residence time, forexample valve trays, preferably bubble-cap trays or related types, forexample tunnel trays or Thormann trays. However, it is also possible touse metal mesh packings or sheet metal packings having an orderedstructure or else to use dumped packing beds as column internals.

In segment (17) above the feed site (3) preferably column internalshaving a high theoretical number of plates such as metal mesh packingsor sheet metal packings having an ordered structure are used.

Furthermore, it is also advantageous, to increase the residence time, topass a part stream through one or more side stream takeoffs (29) fromthe fractionating column (4) through the vessel or vessels (30) and torecirculate the part streams (33) leaving these vessels back to thecolumn (4) using a pump (31) for each. If appropriate, additionalcatalysts and/or reactants can be added to the vessels (30) using a feedline (32).

Heating the vessels (30) is preferred.

To carry out the reaction, advantageously, fractionating columns areused which have as internals typically from 10 to 100 of the traysdescribed in more detail above (16, 17), preferably from 20 to 40 trays.In this case the procedure is advantageously carried out in such amanner that the higher-boiling reactants are introduced into the upperpart of the column and the lower-boiling reactants into the lower partof the column.

It has proved to be particularly advantageous if from 0 to 50 trays,preferably from 5 to 20 trays, are provided in the column above the feedstream (3) for the higher-boiling reactants and from 0 to 50, preferablyfrom 5 to 30, trays are provided in the lower part of the column (16)below the feed stream (3).

The residence time on the column internals should be particularlypreferably approximately 30 minutes. The same applies, correspondingly,for the theoretical plates in the case of other column internals.

A further particularly preferred embodiment of the inventive process isshown in FIG. 2:

In particular in the case of reactions having a high initial rate, itcan be advantageous to connect a reactor (42) upstream of the reactioncolumn and in this manner to reduce the capital costs for the reactioncolumn. For this the chromanol derivative of the formula II (3), theacylating agent (1) and, if appropriate, the catalyst (2) with orwithout preheating are pumped into the preliminary reactor (42). In thisreactor, the reaction firstly proceeds with high initial rate.

In the preliminary reactor, preferably, only a partial conversion issought and the discharge from the preliminary reactor is transportedusing the pump (43) via the line (44) into the downstream reactioncolumn (4).

The reaction column (4), in this embodiment of the inventive process, isessentially designed as described in FIG. 1, in which case the feedpoint of the reactor discharge (44) into the column (4) must be adapatedto the respective system of substances and the conversion rate achievedin the preliminary reactor.

It can also be advantageous to transport into the reactor (42) only apart of the total amount of the acylating agent used and to feed theother part into the reaction column (4) via an additional line (41)below the feed point for the reactor discharge (44). The residence timein the preliminary reactor is advantageously set in such a manner thatthe reaction is run in a reaction range of high reaction rate.

Generally, the residence time in the upstream reactor (42) is from 5minutes to 2 hours, preferably from 15 minutes to 1 hour.

The reactor (42) is symbolized in FIG. 2 as a stirred tank. However,depending on the reaction system, reactors having other residence timecharacteristics, for example tubular reactors or loop reactors are alsopossible.

Using the inventive improved process it is possible to prepare numerouschromanol ester derivatives, in particular tocopherol acetates andtocotrienol acetates which are of importance as antioxidants and in thehuman and animal nutrition sectors, in particular α-tocopherol acetate,at virtually quantitative conversion at very high yields and space-timeyields and high purity.

The inventive process, compared with the prior art, has the followingfurther advantages:

Using the inventive process, selectivities of greater than 99% areachieved, based on the chromanol derivative, and greater than 90%, basedon the carboxylic anhydride. The selectivity based on the carboxylicanhydride is dependent on the purity of the chromanol derivative used,which was 94% in the examples below.

The conversion rate is virtually 100%, based on the chromanolderivative, and 95%, based on the acylating agent, so that only smallamounts of acylating agent need to be recirculated.

The purity of the chromanol ester derivatives is greater than 95% afterremoving carboxylic acid of the formula IIIa and water, or afterremoving carboxylic anhydride of the formula IIIb and the carboxylicacid R9-COOH. This value is also dependent on the purity of thechromanol derivative of the formula II used, since, in particular in thecase of tocopherols and tocotrienols, the product contaminantprincipally found is high-boiling minor components already present inthe tocopherol or tocotrienol used. After removing these components theproduct purity is greater than 99%, so that only very few byproducts areformed in the inventive process.

A further advantage of the process is the continuous procedure whichensures constant non-charge-dependent product quality. The space-timeyield, for comparable acid concentration, is higher by a factor of 3than in the previously known processes. In addition, the heat ofreaction released during the reaction can be utilized for thedistillation and thus energy costs can be saved.

A further great advantage of the inventive process is that the highachievable yields are achieved in a continuous process in a reactor withvirtually quantitative conversion based on all starting components, moreprecisely even if no excess, or only a slight excess, of one of thereactants is used.

In addition, advantageously, no solvents need to be used and thecarboxylic acid R9-COOH which is formed as a byproduct when carboxylicanhydrides of the formula III are used can be further used as a productof value.

The examples below describe the invention

EXAMPLE 1

Preparation of α-Tocopherol Acetate

A Description of the Apparatus

The apparatus used was a fractionating column (4) having 20 bubble-captrays (approximately 14 theoretical stages) below the upper feed point(2) and 0.6 meters of a structured mesh packing (Rhombopak 9M) above theupper feed point (2). The column had an internal diameter of 30 mm. Thetrays were numbered from bottom to top, that is to say the lowest traywas tray 1 and the uppermost tray was tray 20.

The column was fitted with regularly spaced thermocouples, so that inaddition to the bottom and the top of the column the temperature couldbe measured at each 3rd to 4^(th) theoretical stage. In addition to thetemperature profile, using appropriate sampling points the concentrationprofile in the column could be determined.

The evaporator (13) which could be heated using a thermostat to 250° C.had a volume of approximately 350 ml, with the fill level duringoperation, depending on the residence time, being from 50 to 155 ml. Acondenser which was operated by a cryostat was mounted on the column. Inaddition, the column was equipped with a vacuum system (9) and a coldtrap. The bottom discharge (35) of the column was passed to a downstreamthin-film evaporator (19), via the bottom of which the crude product(34) freed from low-boilers was ejected. The distillate of the thin-filmevaporator was condensed in a condenser (21), collected in a vessel (23)and pumped back to the column. On phase breakdown the vessel (23) wasused as separating vessel and the lower phase which contains thecarboxylic anhydride was recirculated to the column. The apparatus wasrun in 24-hour operation (steady state) and all influent and effluentstreams were recorded and displayed using balances.

B Experimental Procedure

Preparation of α-Tocopherol Acetate Without Recycling

74.6 g/h (0.16 mol/h) of α-tocopherol (93.6% pure) and 2.05 g/h of 1%strength sulfuric acid in acetic acid (0.13 mol % sulfuric acid (100%)based on α-tocopherol) were pumped to tray 20 of the column and 21.2 g/h(0.34 mol/h) of acetic anhydride were pumped to tray 3 of the column. Asystem pressure of 400 mbar and a reflux ratio of 2 kg/kg wereestablished.

The bottom temperature was 156° C. and the residence time in the reactorsystem was 3 hours, which was made up of 1 hour on the internals of thefractionating column (16) and 2 hours in the evaporator (36). Thebottoms stream produced from the column was 84.8 g/h of crude productcontaining 94.0% by weight of α-tocopherol acetate and 0.1% by weight ofα-tocopherol. 9.6 g/h of distillate consisting of 100% by weight ofacetic acid were taken off from the top of the column.

α-Tocopherol acetate was produced with a selectivity of 99.9% based onα-tocopherol and 96.7% based on acetic anhydride. The conversion ratewas 99.9% based on α-tocopherol and 84% based on acetic anhydride. Thespace-time yield was about 262 g/(l*h).

EXAMPLE 2

Preparation of α-Tocopherol Acetate Without

Recirculation/Catalyst to Acetic Anhydride (VEA30)

In the apparatus described in example 1,100.0 g/h (0.22 mol/h) ofα-tocopherol (93.6% pure) and 1.9 g/h of 1% strength sulfuric acid inacetic anhydride (0.09 mol % of sulfuric acid (100%) based onα-tocopherol) were pumped to tray 20 of the column and 26.7 g/h (0.26mol/h) of acetic anhydride were pumped to tray 3 of the column. A systempressure of 400 mbar and a reflux ratio of 2 kg/kg were set. The bottomtemperature was 155° C. and the residence time in the reactor system was2.2 hours, which was made up of 0.7 hours on the fractionating columninternals (16) and 1.5 hours in the evaporator (36). The bottoms streamof the column produced was 113.8 g/h of crude product containing 93.7%by weight of α-tocopherol acetate and 0.07% by weight of α-tocopherol.At the top of the column, 11.6 g/h of distillate consisting of 100% byweight of acetic acid were taken off. α-Tocopherol acetate was producedwith a selectivity of 99.9% based on α-tocopherol and 97.9% based onacetic anhydride. The conversion rate was 99.9% based on α-tocopheroland 82% based on acetic anhydride. The space-time yield was about 350g/(l*h).

EXAMPLE 3

Experimental Procedure—Preparation of α-Tocopherol Acetate UsingRecirculation (VEA53)

150.0 g/h (0.33 mol/h) of α-tocopherol (94.9% pure) and 2.1 g/h of 1%strength sulfuric acid in acetic anhydride (0.067 mol % sulfuric acid(100%) based on α-tocopherol) were pumped to tray 20 of the column and35.0 g/h (0.34 mol/h) of acetic anhydride were pumped to tray 3 of thecolumn. A system pressure of 400 mbar and a reflux ratio of 2 kg/kg wereset. The bottom temperature was 164° C. and the residence time in thereactor system was 1.2 hours, which was made up of 0.7 hours on thefractionating column internals (16) and 0.5 hours in the evaporator(36). The bottoms stream of the column was passed to the thin-filmevaporator, the distillate was condensed out and recirculated into thecolumn to tray 3 (recirculated stream 2.2 g/h). The bottom stream of thethin-film evaporator produced was 164.0 g/h of crude product containing94.15% by weight of α-tocopherol acetate and 0.34% by weight ofα-tocopherol. At the top of the column, 16.4 g/h of distillateconsisting of 100% by weight of acetic acid were taken off.

α-Tocopherol acetate was produced with a selectivity of 99.4% based onα-tocopherol and 91.0% based on acetic anhydride. The conversion ratewas 99.6% based on α-tocopherol and 100% based on acetic anhydride. Thespace-time yield was about 700 g/(l*h).

COMPARATIVE EXAMPLE 1

Batchwise Reaction Procedure

The batchwise comparative experiment was carried out in a heated roundbottomed flask equipped with stirrer, thermometer and mounted refluxcondenser. 300.75 g of α-tocopherol (93.6% pure) (0.655 mol calculated100%) were charged into the flask and heated to 100° C. 86.4 g (0.847mol) of acetic anhydride were then admixed with 0.03 g (0.00031 mol) ofsulfuric acid (96% strength) and added to the flask with stirring. Inthe course of this the reaction mixture heated up due to the heat ofreaction released and was then controlled to 140° C. After 2 hours thereaction mixture was cooled to room temperature. The reaction dischargewas analyzed by GC. 299.7 g of α-tocopherol acetate, 0.05 g ofα-tocopherol, 44.3 g of acetic acid and 10.2 g of acetic anhydride werefound in the reaction discharge. α-Tocopherol acetate was produced witha selectivity of 96.9% based on α-tocopherol and 85.0% based on aceticanhydride. The conversion rate was 99.9% based on α-tocopherol and 88%by weight based on acetic anhydride. The total batch time was about 3hours.

We claim:
 1. A process for continuously preparing chromanol ester of theformula I,

where R1, R2, R3, R4, R5, R6, R7 and R8 independently of one another arehydrogen or an unsubstituted or substituted, branched or unbranchedC₁-C₁₀-alkyl radical and the dashed bonds are a possible additional C—Cbond, by reacting continuously fed chromanol of the formula II

with continuously fed an acylating agent selected from the groupconsisting of carboxylic acids of the formula IIIa R8-COOH  IIIa andcarboxylic anhydrides of the formula IIIb,

where R9 is hydrogen or an unsubstituted or substituted, branched orunbranched C₁-C₁₀-alkyl radical, and R8 is as defined above, in areactor and continuously removing the reaction products from thereactor.
 2. A process as claimed in claim 1, wherein at least onereaction product is removed from the reaction mixture during thereaction.
 3. A process as claimed in claim 1, wherein the reactor is areaction column.
 4. A process as claimed in claim 3, wherein thereaction parameters are set in such a manner that A the chromanol of theformula II react with the acylating agent on the internals and possiblyin the bottom phase of the reaction column, B the H₂O formed in thereaction with the carboxylic acids of the formula IIIa or the carboxylicacid R9-COOH formed in the reaction with the carboxylic anhydrides ofthe formula IIIb is continuously removed with the overhead stream of thereaction column and C the chromanol ester of the formula I formed in thereaction are continuously removed with the bottom stream of the reactioncolumn.
 5. A process as claimed in claim 3, wherein a further reactor isconnected upstream of the reaction column.
 6. A process as claimed inclaim 1, wherein the reaction is carried out in the presence of acatalyst.
 7. A process as claimed in claim 3, wherein the reactioncolumn has internals in form of column trays below the highest feedpoint for the reactants, and internals in form of structured packingsabove the highest feed point for the reactants.
 8. A process as claimedin claim 3, wherein the reactants of formula II and of formula IIIa orformula IIIb are separately fed into the reaction column at differentpoints, the reactant having a higher boiling point, optionally togetherwith a catalyst, being fed into the reaction column at a point above thepoint at which the lower-boiling reactant is fed to the column.
 9. Aprocess as claimed in claim 3, wherein heat is fed into the reactioncolumn by means of an evaporator and additionally by means of heatexchangers mounted externally to the reaction column, or by means ofheat exchangers situated directly on internals of the reaction column.10. A process as claimed in claim 3, wherein a stripping gas isintroduced into the reaction column.
 11. A process as claimed in claim3, wherein excess acylating agent is separated from the effluent bottomstream in a downstream evaporator, and the separated acylating agent is,in whole or in part, recirculated to the column.
 12. A process asclaimed in claim 1, wherein the reactor comprises a preliminary reactorand a reaction column, said preliminary reactor being connected upstreamto the reaction column.
 13. A process as claimed in claim 12, whereinheat is fed into the reaction column by means of an evaporator andadditionally by means of heat exchangers mounted externally to thereaction column, or by means of heat exchangers situated directly oninternals of the reaction column, and heat is additionally supplied tosaid preliminary reactor.